Neonatal opioid withdrawal syndrome (NOWS) has increased more than fivefold since 2000. The dramatic rise in NOWS has occurred in association with an increase in the use of opioids by pregnant women. Little is known about the best methods for identification, monitoring, and treatment of affected infants. The IDeA States Pediatric Clinical Trials Network (ISPCTN), which is part of the Environmental influences on Child Health Outcomes (ECHO) Program, and the Neonatal Research Network (NRN) are uniquely poised to address existing knowledge gaps associated with NOWS. The ISPCTN consists of >20 neonatal intensive care units and the NRN consists of >50 neonatal intensive care units. Both networks have access to investigators, study coordinators, infrastructure, and participants for clinical trials. The Duke Clinical Research Institute (DCRI) serves as the ECHO Coordinating Center and has extensive experience in cohort studies and clinical trials in infants. We will also leverage the expertise of the Data Coordinating and Operations Center (DCOC) of the ISPCTN at the University of Arkansas for Medical Sciences (UAMS). The overall goal of our proposal is to use the infrastructure of the ECHO Program and ISPCTN in collaboration with the NRN to initiate two clinical trials to evaluate interventions to improve the care of infants and families affected by NOWS. Our research team, led by Drs. Brian Smith and Rachel Greenberg at DCRI and Drs. Jeannette Lee and Jessica Snowden at UAMS, will achieve this goal by implementing: 1) a clinical trial protocol evaluating the optimal use of the Eating, Sleeping, Consoling (ESC) care approach on the length of time until infants affected by NOWS are medically ready for discharge; and 2) a clinical trial protocol evaluating whether an early stop weaning protocol for morphine in infants treated for NOWS will decrease the number of days of opioid treatment. Using the highest research standards, we will accomplish the task set out by the NIH to close research gaps in this critically important area.